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CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 581

and possibly infectious matter. Pulmonary involvement is typically airway obstruction. Epidemiological studies have shown that
diffuse and consists predominantly of mononuclear inflammation lung cancer risk is strongly related to radiographic emphysema,
of the terminal bronchioles, interstitium, and alveoli, with little independent of air flow obstruction. In contrast, nonsmoking
involvement of the larger airways. Although the term “extrinsic patients with asthma have no greater risk of lung cancer than
allergic alveolitis” is commonly used for this disorder, low-grade the general nonsmoking population.
eosinophilia is only seen in 1–3% of BAL specimens and is not The Global Initiative for Chronic Obstructive Lung Disease
a consistent or characteristic feature of disease. Over time, this (GOLD) has in the past decade promoted the use of a fixed
pattern of inflammation leads to destruction of alveoli and to FEV 1 /forced vital capacity (FVC) ratio of <70% to diagnose
irreversible pulmonary fibrosis that may ultimately be fatal. COPD. This latter guideline is now widely used to classify smokers
The etiology of HP is usually idiopathic, but many cases can be with and without COPD, but it excludes up to 20% of smokers
traced to exposure to organic aerosols that contain thermophilic with emphysema who have normal lung function, and it under-
bacteria (e.g., Saccharopolyspora rectivirgula), filamentous fungi diagnoses and overdiagnoses COPD in young and old smokers,
(e.g., Aspergillus spp.), animal proteins and fecal matter (e.g., respectively. Recognizing different COPD phenotypes based on
pigeon breeder’s disease), and industrial chemicals, such as isocya- lung function, symptom severity, and exacerbation frequency,
nates. Symptoms, including chest tightness, chest pain, dyspnea, smokers are categorized into one of four stages: (A) fewer
and fever, appear 4–6 hours after exposure. Cessation of exposure symptoms, low risk; (B) more symptoms, low risk; (C) fewer
to the provoking antigen may prevent progression to chronic, symptoms, high risk; (D) more symptoms, high risk. Those in
irreversible disease. Other than oxygen therapy in the setting groups C and D are thought to benefit from inhaled corticosteroids
of profound hypoxemia, there is no defined medical therapy in addition to bronchodilators. 40
for HP; in particular, there is no role for glucocorticosteroids. Smokers with emphysema have enlarged alveoli that contain
The immunopathogenesis of HP is complex and not well increased numbers of macrophages containing nano-sized elemen-
understood. During the acute presentation, the histological picture tal carbon black (nCB). The key property underlying the initiation
is an immune complex–mediated interstitial injury with a of destructive lung inflammation with nCB inhalation appears to
predominant neutrophilic infiltrate. Subsequently, the disease be its chemical characteristics, namely, its insolubility and small
evolves into predominant mononuclear inflammatory infiltrates particle size that activate the inflammasome pathway and promote
consisting of lymphocytes, plasma cells, and foamy macrophages, differentiation of lung Th1 and Th17 cells. nCB can be readily
followed by granuloma formation. In advanced disease, the detected in lung phagocytic cells (e.g., DCs and macrophages) by
inflammatory infiltrates are replaced by fibrosis. using Raman spectroscopy and electron microscopy (Fig. 41.8). 41
Acutely, HP is thought to be initiated by an immune-complex The treatment of emphysema is largely supportive, comprising
mediated hypersensitivity (type III) with in situ immune complex bronchodilators and cholinergic antagonists, which suppress
deposition in the lung interstitium as a result of interaction of mucus production, and inhaled or systemic glucocorticosteroids,
the inhaled antigen and preexisting IgG antibodies in the alveolar
spaces. Complement activation occurs and most likely contributes
to the alveolitis and neutrophilia. However, many people with
precipitating antibodies to putative HP antigens (precipitins)
do not develop actual parenchymal or symptomatic disease.
Therefore it is believed type IV, delayed-type hypersensitivity
reactions involving Th1 and possibly Th17 cells also contribute
to disease expression. 38
Chronic Obstructive Pulmonary Disease
The disorder most frequently confused with asthma is chronic
obstructive pulmonary disease (COPD), which encompasses
chronic bronchitis with or without emphysema. COPD is currently
the fourth leading cause of death in the world but is expected
to reach third place by 2020. The most common cause of COPD
is active tobacco smoking, but chronic exposure to coal dust,
biomass fuels, second-hand smoke, and chronic respiratory
infections have been linked to COPD in nonsmokers. Because
not all smokers develop COPD, disease initiation is thought to
reflect interaction of genetic susceptibility and environmental
factors. Development of early-onset emphysema in highly sus-
ceptible smokers is sometimes caused by undetected mutations 1 µm
in the α 1 antitrypsin (A1AT) gene locus (e.g., ZZ, MZ, MS).
However, in the vast majority of individuals, the genetic factors
responsible for increased susceptibility to emphysema remain
unknown. Indeed, several large studies have shown that although
multiple genes contribute to increased risk of emphysema, each FIG 41.8 Nanoparticulate Carbon Black (nCB) Accumulation
individual gene shows only a modest and independent effect. 39 Within an Alveolar Macrophage. Electron micrograph of an
In addition to cough and sputum production, COPD often alveolar macrophage isolated from the peripheral lung of a ciga-
presents clinically with insidious onset of dyspnea and progressive rette smoker with emphysema. Arrow points to a vacuole contain-
and persistent exercise limitation, with minimal reversibility of ing nCB.